Hereditary xerocytosis (HX, MIM 194380)is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. Copy number analyses, linkage studies, and exome sequencing were used to identify novel mutations affecting PIEZO1, encoded by the FAM38A gene, in 2 multigenerational HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all affected persons in both kindreds. All patients were heterozygous for FAM38A mutations, except for 3 patients predicted to be homozygous by clinical and physiologic studies who were also homozygous at the DNA level. The FAM38A mutations were both in residues highly conserved across species and within members of the Piezo family of proteins. PIEZO proteins are the recently identified pore-forming subunits of channels that mediate mechanotransduction in mammalian cells. FAM38A transcripts were identified in human erythroid cell mRNA, and discovery proteomics identified PIEZO1 peptides in human erythrocyte membranes. These findings, the first report of mutation in a mammalian mechanosensory transduction channel-associated with genetic disease, suggest that PIEZO proteins play an important role in maintaining erythrocyte volume homeostasis. IntroductionHereditary xerocytosis (also known as HX or dehydrated stomatocytosis, DHSt; OMIM 194380) is an autosomal dominant hemolytic anemia characterized by primary erythrocyte dehydration. 1 HX erythrocytes exhibit decreased total cation and potassium content that are not accompanied by a proportional net gain of sodium and water. HX patients typically exhibit mild to moderate, compensated hemolytic anemia. Erythrocyte mean corpuscular hemoglobin concentration is increased and erythrocyte osmotic fragility is decreased, both reflecting cellular dehydration.A locus for HX on chromosome 16 (16q23-q24) was first identified in a large, 3-generation Irish family. 2 This locus was refined to D16S511-16qter via study of 10 kindreds with variants of HX, pseudohyperkalemia, or nonimmune hydrops fetalis. 3,4 Recent studies of one of the original HX families from Rochester, NY, 5 and of a large HX family from Manitoba, Canada 6 confirmed the linkage of the disease phenotype to chromosome 16q, and refined the candidate region to 16q24.2-16qter, a 2.4 million-bp interval containing 51 known or predicted genes. 6 To identify the HXassociated genetic locus, we performed high-resolution single nucleotide polymorphism (SNP) typing and whole-exome sequencing on selected persons from both the New York and Canadian HX kindreds.In the refined candidate region, no regions of copy number variation were detected at 16q24.2-16qter. A large region of homozygosity was detected in this region in DNA from a presumed homozygote from the New York kindred. Exome sequencing identified novel mutations affecting PIEZO1 (encoded by the FAM38A gene) in both HX kindreds. Segregation analyses confirmed transmission of the PIEZO1 mutations and cosegregation with the disease phenotype in all...

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IntroductionSepsis and septic shock are leading causes of intensive care unit (ICU) mortality. They are characterized by excessive inflammation, upregulation of procoagulant proteins and depletion of natural anticoagulants. Plasma exchange has the potential to improve survival in sepsis by removing inflammatory cytokines and restoring deficient plasma proteins. The objective of this study is to evaluate the efficacy and safety of plasma exchange in patients with sepsis.MethodsWe searched MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, and grey literature for relevant citations. We included randomized controlled trials comparing plasma exchange or plasma filtration with usual care in critically ill patients with sepsis or septic shock. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was all-cause mortality reported at longest follow-up. Meta-analysis was performed using a random-effects model.ResultsOf 1,957 records identified, we included four unique trials enrolling a total of 194 patients (one enrolling adults only, two enrolling children only, one enrolling adults and children). The mean age of adult patients ranged from 38 to 53 years (n = 128) and the mean age of children ranged from 0.9 to 18 years (n = 66). All trials were at unclear to high risk of bias. The use of plasma exchange was not associated with a significant reduction in all-cause mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.45 to 1.52, I2 60%). In adults, plasma exchange was associated with reduced mortality (RR 0.63, 95% CI 0.42 to 0.96; I2 0%), but was not in children (RR 0.96, 95% CI 0.28 to 3.38; I2 60%). None of the trials reported ICU or hospital lengths of stay. Only one trial reported adverse events associated with plasma exchange including six episodes of hypotension and one allergic reaction to fresh frozen plasma.ConclusionsInsufficient evidence exists to recommend plasma exchange as an adjunctive therapy for patients with sepsis or septic shock. Rigorous randomized controlled trials evaluating clinically relevant patient-centered outcomes are required to evaluate the impact of plasma exchange in this condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0699-2) contains supplementary material, which is available to authorized users.